Until recently, a majority of studies of bone fracture resistance focused on bone mass. However, epidemiological studies now suggest that a significant proportion of fracture risk is independent of bone mass. In addition to the effects of age and sex, proxy measures of bone strength (e.g. bone mineral content and density) consistently show significant genetic effects. While genetic studies of bone material properties have been conducted in rodents, similar studies have not been done in humans or other primates. Substantial differences in fracture properties between other species and primates underscore the need for a genetically well-characterized non-human primate model for studies of the genetics of bone material properties. We propose to investigate the contribution of genes to cortical bone material properties, direct measures of bone quality that are essential aspects of a bone's structural integrity. The ultimate objective of the proposed study is to establish the baboon as a model for the genetic study of human bone material properties. Using data collected from the right femur of 100 pedigreed adult baboons, the specific aims of this project are to: 1) determine cortical bone tissue properties including elastic modulus, yield and ultimate strength, post-yield behavior, fracture toughness, and mineralization (ash fraction and microCT-determined bone mineral density) and determine the degree to which cortical bone density and mineralization (ash fraction) are correlated to cortical bone material properties; 2) characterize normal variation, including age and sex effects, on cortical bone material properties in the baboon; and 3) detect and quantify the proportion of variation in these properties that is due to the additive effects of genes. We will assess the relative magnitude of the effect of genes on cortical bone properties as determined in this project vs. trabecular bone material properties determined from other research. Demonstrating that cortical bone material properties are heritable is an essential step leading to future studies to detect, localize, and identify the specific genes that effect these properties in the baboon. Phylogenetic proximity and consequent similarities in skeletal physiology and genetics between baboons and humans inspire confidence that these results will be directly relevant to humans. This project is consistent with the National Institute of Arthritis and Musculoskeletal and Skin Diseases' mission of supporting research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases as the goal is to establish a non-human primate model that will lead, ultimately, to improved understanding of the genetic regulation of bone material properties that will facilitate earlier identification of persons at greater risk for fracture (due to osteoporosis-associated skeletal fragility), and allow earlier implementation of prevention and treatment strategies. Osteoporosis is an age-related health problem of immediate public health concern that results in 1.5 million fractures in the U.S. each year. A great deal of the risk of osteoporotic fracture is due to genes. We propose to develop the baboon as a nonhuman primate model for the genetics of cortical bone fragility in humans. Establishment of this model will lead, ultimately, to improved understanding of the genetic regulation of these material properties, thereby facilitating earlier identification of persons at greater risk for fracture, and allowing for earlier implementation of prevention and treatment strategies. [unreadable] [unreadable] [unreadable]